O,n-diphenyl-carbamic acid esters

ABSTRACT

Certain O,N-diphenyl-carbamic acid esters in which one phenyl moiety is substituted in the 2-position by a halogenated phenoxy radical are disclosed as microbicidally active compounds. A method for controlling microorganisms with the aid of such compounds and compositions containing them are also described.

Traber et al.

O,N-DlPHENYL-CARBAMIC ACID ESTERS Inventors: Walter Traber, Riehen; Heinz Hambock, Binningen; Anton Georg Weiss, Benken, all of Switzerland Assignee: Ciba-Geigy Corporation, Ardsley,

Filed: Jan. 26, 1970 Appl. No.: 5,954

[ 1March 20, 1973 [56] References Cited UNITED STATES PATENTS 3,371,109 2/1968 Baker et al ..260/47l C Primary Examiner-Henry R. .liles Assistant Examiner-L. Arnold Thaxton Att0 rneyKarl F. Jorda and Frederick H. Rabin 57] ABSTRACT Certain O,N-diphenyl-carbamic acid esters in which one phenyl moiety is substituted in the 2-position by a halogenated phenoxy radical are disclosed as microbicidally active compounds. A method for controlling microorganisms with the aid of such compounds and compositions containing them are also described.

9 Claims, No Drawings O,N-DIPHENYL-CARBAMIC ACID ESTERS The present invention concerns new O,N-diphenylcarbamic acid esters, process for the production of these compounds as well as compositions and methods for the control of microorganisms employing the new carbamic acid esters.

The new O,N-diphenyl-carbamic acid esters (carbanilic acid-phenyl esters) correspond to the Formula I In this formula:

R represents a phenoxy radical substituted by at least one and at most three identical or differing halogen atoms,

of the symbols R R and R at least one represents chlorine or bromine, the others each independently represent hydrogen, chlorine or bromine,

R and R each independently represent hydrogen, halogen, lower alkyl, lower alkoxy, lower halogenalkyl, nitro or hydroxy,

R represents hydrogen, halogen, lower alkyl,

lower alkoxy, dialkylamino, hydroxy, and

X represents oxygen or sulfur.

in Formula I, R is in particular one of the following halogenated phenoxy radicals: 4-chlorophenoxy, 4- bromophenoxy, 2,4-dichlorophenoxy, 2,4- dibromophenoxy, 2,4,5-trichlorophenoxy.

Lower alkyl and lower alkoxy radicals R to R have from one to four carbon atoms. As halogenalkyl, trifiuormethyl is preferred. The alkyl substituents in a dialkylamino group are radicals having one to four carbon atoms in particular the methyl radical. By halogen represented by R R and/or R is meant fluorine, chlorine, bromine and iodine, especially however, fluorine, chlorine and/or bromine.

The new O,N-diphenyl-carbamic acid esters are obtained according to the invention, either (a) by converting a phenol of the Formula ll as such or in the Form of one of its alkali metal or alkaline earth metal salts,

with phosgene or thiophosgene into an acid chloride of the Formula III R? R4 A EGO-fi-Cl X B (III) and reacting this with an aniline of the Formula IV N1] [in I l/ 9 or (b) in those cases in which X represents oxygen, by reacting said phenol of Formula II, as such or in the form of one of its alkali metal or alkaline earth metal salts,

with a phenyl isocyanate of the Formula V In the Formulas I to V, the symbols R to R and X have the meanings given for Formula I.

The process according to the invention is preferably carried out in the presence of a solvent or diluting agent and of an acid-binding agent (proton acceptor).

Examples of suitable solvents or diluting agents are: hydrocarbons, such as toluene, benzene or ligroine, halogenated hydrocarbons, such as chloroform, carbon tetrachloride or chlorobenzene, amides such as dimethylformamide, ethers and ether-like compounds such as tetrahydrofuran, dioxan or diisopropylether, ketones such as acetone or methyl-ethylketone. Acidbinding agents are preferably organic bases, e.g., tertiary amines such as pyridine, triethylamine etc., inorganic bases such as the hydroxides and carbonates of alkali metals and alkaline earth metals.

In the following examples, the production of some of the diphenyl-carbamic acid esters of Formula I is described. The temperatures are given in degrees centigrade.

EXAMPLE 1 a. About g of phosgene are introduced at 0 into 500 ml of toluene. To this solution there is added dropwise at 0 to 5, a solution of 289.5 g of 4,2,4- trichloro-2-hydroxy-diphenyl ether in 700 ml of toluene, and 100 g more of phosgene are introduced. While stirring, a solution of l l 1.3 g of triethyl amine in 200 ml of toluene is then added to the reaction mixture. After standing for several hours at room temperature, the excess phosgene is removed, the triethylaminehydrochloride is separated, and the solvent is removed from the filtrate. The residue is fractionated, the 0-[2- (2 ,4'-dichlorophenoxy)-5-chlorophenyl] carbohyl chloride boils at l 84 and 0.5 Torr.

b. 35.2 g of 0-[2-(2,4'-dichlorophenoxy)-5- chlorophenyl]-carbonyl chloride, dissolved in 300 ml of acetone, are treated dropwise at 15 to 20 with a solution of 32.4 g of 3,5-dichloraniline in 150 ml of acetone. The reaction mixture is then allowed to standv for 3 hours at room temperature, poured onto water, and the precipitate which separates out after several hours is removed by filtration. After recrystallizing several times from cyclohexane and benzene/pteroleum ether, N-(3,5-dichlorophenyl)-carbamic acid-0-[2- (2 ,4-di-chlorophenoxyl)-5-chlorophenyl]-ester having a melting point of 1 32 134 is obtained.

EXAMPLE 2 a. A solution of 150 g of thiophosgene in 400 ml of chloroform is added to a solution of 289.5 g of 2',4- dichloro-2-hydroxy-4-chloro-diphenyl ether in 400 ml of chloroform, and cooled to 5". While stirring vigorously, an aqueous sodium hydroxide solution, 50 g of sodium hydroxide dissolved in 790 ml of water, is

tridium tetani, Klebsiella pneumoniae, Alcaligenes faecalis, Sarcina spec., Salmonella pullorum, Salmonella typhi, Salmonella paratyphi A and B, Salmonella typhimurium, Salmonella enteritidis, Shigella dysenteriae, Shigella flexnerl, Brucella abortus, Proteus mirabilis, Achromobacter spec., Serratia marcescens, Pasteurella pseudatuberculosis. The compounds of Formula I also have very good activity against fungi, for example against the following fungi: Aspergillus spec. e.g., Aspergillus niger, Aspergillus flavus, Aspergillus fizmigatus,

Candida spec. e.g., Candida albicans, Candida tropicalis,

Peneillium spec., for example Penicillium italicum, Penicillium chrysogenum, Epidermophyton spec.,

Trichophyton spec., Ctenomyces spec., Keratinomyces spec., Blastomyces spec., Microsporum spec., Cryptococcus neoformans var., Torulopsis spec., Altemaria tenuis, Acrostalagmus cinnabarinus, Fusarium 0xysporum, cellulose-degrading fungi, wood fungi, etc.

O-phenoxyphenyl-N-trifluoromethylphenyl carbamic acid esters which are unsubstituted in the phenoxy group are embraced by the Dutch Pat. application open to public inspection No. 6,606,753 as anthelminths, not however being described. These compounds however have no, or only very weak microbicidal properties. In addition a series of O-halogenophenyl-N-phenyl-carbamic acid esters or O-phenyl-N-halogenophenyl-carbamic acid esters are described as herbicides and for use in plant protection. These compounds are, however, due to their lack of effect or lack of broad enough range of action, unsuitable, especially for the control of pathogenic microorganisms, for example of the urinal track and intestines of warm-blooded animals.

To determine the bacteriostatic and fungistatic action of the compounds of Formula I, the following microorganisms were used:

A. Bacteria Escherichia coli, Bacillus pumilus, Sarcina ureae, Bacillus subtilis, Sarcina lutea, Streptococcus faecalis, Staph. saproph., Staph. aureus, Corynebact. diphtheroides l7, Brevibact. ammoniagenes, Salmonella pullorum, Proteus vulgaris HXL, Proteus vulgaris 0x 19, Proteus mirabilis; B. Fungi 1a Aspergillus niger, Penicillium italicum, Fusarium 3 facultative Dermatophytes Trichophyton gypseum,

C tenomyces spec., Keratinomyces ajelloi, Epidermophytonfloccosum, 4 ubiquitous Saprophytes: Rhizopus nigricans,

Paecilomyces varioti, Penicillium citrinum, Aspergillus oryzae, Aspergillus clavatus, Aspergillus flavus.

5 Fungi imperfecti: Scopulariopsis brevicaulis, Alternaria tenuis, Acrostalagmus cinnabarinus,

6 Coniophora cerebella, Poria vaporaria, Poria incarnata,

7 Polystictus versicolor, Daedelea quericina, Lencites abietinam Lentinus lepideus,

8 parasites: Fomes annosus 9 blue stain: Scoplularia phycomyces, Pullularia pullulans. C. Method The lowest growth-inhibiting concentration for the various microorganisms was determined by mixing the solution of active substance with nutrient agar while still warm. The agar is then poured into plates and, after solidification, inoculated with the test germs.

In the following table are listed: the nutrient media used for the various organisms, the incubation temperature and incubation time, as well as the concentration of the active substances used:

* ppm: parts of active substance per 10 parts of agar In the following Table 2, the bacteriostatic action,

oxysporum, Candida albtcans, Stemphyltum and in Table 3, the fungistatic action of some of the botryosum, compounds listed in Table l on some of the previously lb cellulose-degraders: Chaetomlum globosum, listed microorganisms are given.

TABLE 2 Staph- Stnph- Slaphylococylococ Strep- Coryne- Brevz- Esch e ylococcus cus Sarcina tacoccus ba bacterium riclua Salmo- Compound cm aureus saproph. Bacillus Bacillus lutea faecalir diphammon. cola nella number aureus ATCC N CTC pumilus sublilis Sarcina. NCTC NCTC teroides ATCC NCTC pulloru'm Proim Table 1 SG 511 6538 7292 Fey NCTC urcae 1 8619 17 68 81 VBI ap 10 30 3 10 10 30 30 30 30 1 10 10 10 10 3 10 10 30 30 30 30 10 1 10 10 1 30 10 10 10 10 30 30 30 30 1 10 10 1 30 30 10 10 10 30 30 30 10 l 30 10 1 l0 3 10 10 10 30 30 10 10 1 10 10 3 10 3 3 10 10 30 10 10 10 1 10 10 1 3 3 3 10 8 3 3 3 1 1 10 10 1 30 30 l0 l0 30 30 30 30 1 30 10 3 10 10 10 10 10 30 30 10 10 10 10 10 1 10 10 10 10 30 30 30 30 l 10 10 10 10 10 10 10 10 30 30 10 l0 l0 10 10 3 3 10 1 10 10 30 10 10 3 l0 10 30 3 3 3 l 10 3 3 3 10 3 3 30 30 3 3 3 l 3 10 30 3 l0 3 10 30 30 1 1 3 1 3 3 3 3 l0 1 10 10 10 3 3 3 I 3 10 30 10 10 3 l0 10 30 1 3 1 3 3 10 10 10 1O 10 1 10 10 1 3 1 3 3 10 10 10 10 10 1 10 10 1 10 3 3 3 10 30 10 10 10 l 10 10 Brcvi- Eschebact. bacterium richia Salmodiphcoli nella leroides AT C C N CT 0 pulloru'm Proteus 6871 8196 VBIZ TABLE z Continued Strep- Corone- Sarcimz tococcus Bacillus lutea fuecalis ammon.

subtilis Sarcina NCTC NCIC Fey NCTC ureae 196 8619 17 Staphylococ cus saproph. Bacllius NCTC pumilus Staph- Staphylococylococcus cus aureus aureus ATC C S G 511 6538 Compound number Table 1 a s 000 00000000000000000000000000000000 00 .m Mn 333 3033333133333 333333333333333333MNMN33MMMM m um 1 0 P 0 00 mmmmwmmm .mwmmmmmm1mmmmm mmm wi A I. z 0000000000000000000 0 000 0 l) u m W d 3333333333111111111 m1 1H1 vlmwwmmwm nmmmmmwflwwufl fi odmmdmmm mm nwm m 11111111 H u 1 1 1 u fl 000000003000000 0000001. 3 .3 3 11111111 11111111111 1 "H u u n 8 000000 .000000000000 0 000 .00 000 0 h hum 333333 m33w33333113 3 33 33 m333w3 Q XNM WNWNMWW m n m M v 000 00 0001 "013 P H n n u u 111111 H u u n n H u 0000000000000000000 .0 .000 .00000000 .00000000000 n n n w 1110 11131313111111 .1 .131 33311113 3013311111 H M A M m m m 0 11 1 m mwmmm mmmmmlmwm i mm w 00000000000000000000000000000000000000000000 n be 1111111111111111111111111111111111111111.1111111 0 m m ww w3w3w3333 mm33 3 3 3313313 3 0 00000000000 0000000 000 00000000000000 00 E m 3m333333333N3133333w333mm33333333333333 33 L do nim B ab 3 m333m13333333333 333 M M 00 00000000 0 mWm 3N3313 333w1w 0H mmm 0010301 011 11011100 111113313 .m 0 0 00 mm 0%.w033 9mm 1 1 PH. M

Aspargillus fluvus r81 0000000000000000000 u 0000000000030303003 MPH-.1 11111111111 1 1 11 M u r. H

H mm

O ua CDNT 1 a. Bacteria: Escherichia cali, Bacillus pumilus, Sarcina ureae Staphylococcus aureus, Proteus vulgaris HXL. 65 b. Fungi: Aspergillus niger, Fusarium oxysporum, Candida albicans, Saccharomyces cerevisiae (yeast), Torula utilis (yeast).

The bacteriostatic and fungistatic activity of the compounds according to the invention was further determined by the following comparative tests using the method described under (C) above.

The following microorganisms were used Test 1 Test 2 Bacteria: Escherichia coli, Salmonella pullorum, Proteusv vulgaris HX L.

The nutrient media used for the various organisms,

The disinfectant effect of the compounds according to the invention was determined by means of the following tests A. Germ Count in the Rinse Bath the incubation temperature and incubation time, as 5 The third rinse bath containing the active substance well as the concentrations of the active substances used to be tested was inoculated with Staphylococcus aureus are listed in the following table: SG 511 and Escherichia coli. One ml of this bath was added to 20 ml nutritive agar prepared according to Organism Nutrient Incubation Concentration of MacConkey [DifCO Manual 9th EdlllOl'l, (1953), page med'um temp time 2: 32: 10 131] when testing Escherichia coli and to 20 ml nutria) Bakteria Nutrient-Agar 37 48 hr 3040-11-1 tive agar to which 0,5 percent by weight of potassium 1000-300-100 dde w h b) Fungi L NumenMgar 48 hr 10040404 tellurite had been a d hen testing Stap ylococcus 1000.300 aureus SG 511. The resultant mixture was put into Wort-Agar 5 y- Petri dishes which were incubated for 24 hours at 37 15 c Th bl '1 f b h L6 ppm: Part of active substance per 10' parts of agar. i 6 germ count P m1 0 at was determmed by counting the number of colonies formed As comparative substances were used the following the g p The results are compiled Table corn ounds:

P TABLE 6 A N-( 3-tr1fluoromethylphenyl )-carbam1c I Bacterium Staphylococcus Escherichia acid-0-( 2-phenoxypheny l)-ester known from aureu: SG 51 l coli N-( 3 ,5 -bis-trifluoromethylphenyl )-carbamic British acid-0-(2-phenoxyphenyl)-ester Pat. No. C N-( 3-trifluoromethylphenyl )-thiocarbamic 1,139,343 concentration acid-O-(Z-phenoxyphenyl)-ester 1n ppm 6,2 6,2 25 D N-(3-trifluoromethyl-fi-chlorophenyl)-thi- 2 5 Compound No. ocarbamic acid-0-(2-phenoxyphenyl)-ester) (Table E mixture of toluene-2,6- and -2,4-bis-( penta- 3 0 0 l 0 chlorophenyl)-carbamate (British Pat. No. 5 O 0 0 0 1,122,444 10 0 0 0 0 F hexamethylene-di-(pentachlorophenyl)- 46 0 O l 0 carbamate 0 O 6 0 (British Pat. No. 1,122,444). 53 0 0 1 0 G 3,d-dichlorophenyld.4-dichlorocarbanilate 55 0 0 0 0 (115. Pat. No. 3,142,646). E 105 0 I0 10 F 10 10 10 10 G 10 10 10 10 In the following Table 4 are g1ven the results of Test Control 10 10 10 10 1 and in Table 5 those of Test 2. The figures indicate those concentrations, at which no growth can be deter- 1 part active substance per 10" parts rinse bath minated. B. Rinse Bath Disinfection Test TABLE 4 Bacteria Fungi Slaphyl- Eacher- Fu- Sacococcus Bacillus ichia Aspersarium charaaureus pumilus Sarci'na N CIC Proteus glllus ozy- Candida myces Torula SG 511 Fey ureae 8196 vulparis niger sporum albicanr cercviaae utilis a 10 10 1 10 100 10 :10 100 100 1 3 a 1 10 100 30 30 100 100 1 3 10 1 10 100 30 30 a0 a0 a 1 a 10 30 a0 10 a0 30 a0 a 1 a 3 30 30 so 30 so 30 1 3 1o 1 10 100 30 30 100 30 1 1 a 1 10 a0 10 30 30 30 1 a 10 1 10 30 10 30 a0 a0 1 1 10 10 10 30 10 30 30 30 Control. 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,'000

Raw, unfinished cotton fabric which had not been treated with optical brightening agents was rinsed in the bath described under (A). The cotton fabric was punched into disks of 2.5 cm in diameter. These disks were placed each on one agar plate prepared according to MacConkey, supra, thereby using nutritive agar and nutritive agar containing 0,5 percent by weight of potassium tellurite depending on whether the tests are performed with Escherichia coli or Staphylococcus aureus SG 51 l. The agar plates (in Petri dishes) were then incubated for 24 hours at 37 C. The growth on the agar plates was then evaluated visually. The results are compiled in Table 7 wherein represents growth under the textile sample represents no growth under the textile sample 1 represents traces of growth under the textile sample.

Table 7 Bacterium Escherichia coli Staphylococcus aureus SG 51 1 Concentration in ppm Compound No. (Table l) Control 1 part active substance per parts rinse bath C. Inhibition Test Ten ml of Bacto-Agar (Difco No. B 140) were each poured into Petri dishes. 10 ml of molten agar prepared as stated under A) above and inoculated with Staphylococcus aureus SG 51 1 and Escherichia coli were overlaid on each of the Petri dishes containing the Bacto-Agar. Cotton fabric disks treated according to (B) above were, after drying, each laid on a Petri dish, which was then incubated for 24 hours at 37 C. Thereafter, the zone wherein all growth of the bacteria had been inhibited were assessed in millimeters. The results obtained are given in Table 8, wherein signifies growth under the textile sample signifies no growth under the textile sample 1 signifies traces of growth under the textile sample L6 1 part active substance per 10 parts rinse bath The diphenyl-carbamic acid esters of Formula I, produced according to the invention, have a broad and varied range of application for the control of microorganisms, especially of bacteria and fungi, and for the protection of organic materials and objects against attack by microorganisms. Thus, they can be directly worked into the material to be protected, for example into synthetic resin materials such as polyamides and polyvinyl chloride, into baths for the treatment of paper, into thickeners for printing inks, consisting of starch or cellulose derivatives, into lacquers and paints,

containing casein for example, into cellulose, into viscose spinning masses, into paper, into animal mucilages or oils, into polyvinyl alcohol based permanent sizing agents, into cosmetic articles, into ointments or 5 powders. In addition they can be added to preparation of inorganic or organic pigments for painters,

plasticizers, etc. Tlie new compounds are especially valuable for the protection of textiles of all kinds, e.g., Y textiles based on cellulose and keratin material, since they are notably substantive to such fiber materials.

In still other application forms, the carbamic acid esters of Formula I can be employed dissolved in organic solvents, for example as so-called sprays or as dry cleaners or to impregnate wood, the organic solvent being preferably non-miscible with water, in particular petroleum fractions; but also water-miscible solvents such as lower alcohols, for example methanol or ethanol, or ethylene glycol monomethyl or monoethyl ether are suitable.

In addition, they can be employed together with wetting or dispersing agents in the form of aqueous dispersions, for 7 example for the protection of substances which tend to rot such as for the protection of leather, paper, etc.

Solutions or dispersions of the active substances, which can be employed for the protection of these materials, preferably have a concentration of active substance of at least 0.005 g/lit'er.

A preferred field of application of the diphenyl carbamic acid esters of Formula I is the disinfection of washed goods and for the protection of washed goods against attack by microorganisms. For this purpose rinse baths are used containing the said carbamic acid esters, advantageously in concentrations of about 5 to 200 parts per million, calculated on the bath.

The bath can, in addition, also contain other usual auxiliaries such as optical brighteners, softeners, acidreacting salts such as ammonium or zinc silicofiuoride or certain organic acids such as oxalic acid, also finishing agents, for example those based on synthetic resins or starch.

Suitable as wash goods which can be disinfected with rinse baths containing the compounds according to the invention are primarily organic fiber materials, namely that of natural origin such as cellulosic material, e.g., cotton; or polypeptide material, e.g., wool or silk; or synthetic fiber'material such as that based on polyamide, polyacrylonitrile or polyester; or mixtures of the above fibers.

The carbamic acid esters according to the invention in the concentrations given, impart to the bath as well as to the treated wash goods a broad and long-lasting disinfection against Staphylococcus and -Coli forms, which continues even after exposure of the active substance or the goods treated therewith to light. They are distinguished by their high stability to light on the goods treated therewith as well as by their high activity and broad range of action against gram-positive and gram-negative organisms.

The new carbamic acid esters are also veryeffective against the bacterial flora causing perspiration odor, and for that reason and because of their slight toxicity, they are suitable as deodorants for laundry or as additives for cosmetic agents such as ointments or creams.

Especially valuable is the use of the new carbamic acid esters of Formula I produced according to the invention as active substances for the healing of diseased conditions of the skin, the intestinal system and the urinal track of warm-blooded animals, which is possible due to their excellent action against pathogenic bacteria and fungi, their relatively low toxicity, as well as the fact that they are largely excreted from the body in an unchanged, active form.

The antimicrobial compositions according to the invention contain at least one diphenyl carbamic acid ester of Formula I as active ingredient, together with the usual pharmaceutical carriers. The type of carrier depends to a large extent on the intended use. Ointments, powders and tinctures are especially suitable for external application, for example for the disinfection of healthy skin as well as for the disinfection of wounds and for the treatment of dermatoses and affections of the mucous membranes which are caused by bacteria or fungi. The ointment bases can be anhydrous, e.g., they can consist of mixtures of wool fat and vaseline, or they can consist of aqueous emulsions in which the active substance is suspended. Suitable carriers for powders are, e.g., starches, such as rice starch, the bulk weight of which, if desired, can be made lighter, e.g., by the addition of the highly dispersed silicic acid, or heavier by the addition of talcum. Tinctures contain at least one diphenyl carbamic acid ester of Formula I in aqueous ethanol, in particular 45-75 percent ethanol, to which, if desired, 10-20 percent glycerin may be added. Solutions prepared from the usual solubility promoters such as, e.g., polyethylene glycol, as well as optionally, from emulsifying agents, re used in particular for the disinfection of healthy skin. The content of active ingredient in the above forms for external application is preferably between 0.1 and percent.

Suitable for the disinfection of the mouth and throat are gargles, or concentrates for the preparation thereof, in particular prepared from alcoholic solutions containing about 1-5 percent of active substance to which glycerin and/or flavorings can be added, and also lozenges, i.e., solid dosage units, having a relatively high content of sugar or similar substances and a relatively low content of active substance of about 0.2 20 percent, as well as the usual additives such as binding agents and flavorin gs.

For intestinal disinfection and for the oral treatment of infections of the urinal tract, in particular solid dosage unit forms such as tablets, dragees and capsules are suitable, which preferably contain between percent and 90 percent of a diphenyl carbamic acid ester of Formula I to enable the administration of daily doses of between 0.1 and 2.5 g to adults or of suitably reduced doses to children.

Tablets and dragee cores are produced by combining the carbamic acid esters of Formula I with solid, pulverulent carriers such as lactose, saccharose, sorbitol, maize starch, potato starch or amylopectin, cellulose derivatives or gelatin, preferably with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weight. Dragee cores are then coated, for example, with concentrated sugar solutions which may also contain, e.g., gum arabic, talcum and/or titanium dioxide, or they are coated with a lacquer dissolved in volatile organic solvents or mixture of solvents. Dyestuffs can be added to these coatings, e.g., to differentiate between varying dosages. Perles (pearl-shaped, sealed gelatine capsules) and other closed capsules consist, for example, of a mixture of gelatin and glycerin, and contain, e.g., mixtures of a new carbamic acid ester of Formula I with polyethylene glycol. Hard gelatine capsules contain, for example, granulates of an active substance with solid pulverluent carriers such as, e.g., lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, cellulose derivatives or gelatin, as well as magnesium stearate or stearic acid.

In all of the forms of administration, whether for technical, cosmetic, hygienic or medical use, the new diphenyl carbamic acid esters of Formula I can be present as sole active ingredient or they can be combined with other known antimicrobial, in particular antibacterial and/or antimycotic substances, for example to broaden the range of application. They can be combined, for example, with halogenated salicylic acid alkyl amides and anilides, with halogenated diphenyl ureas, with halogenated benzoxazoles or benzoxazolones, with polychlorohydroxy-diphenylmethanes, with halogen-dihydroxy-diphenyl sulfides, with bactericidal Z-imino-imidazolidines or tetrahydropyrimidines or with bactericidal quaternary compounds or with certain dithiocarbamic acid derivatives such as tetramethyl-thiuram disulfide. Optionally, carriers having themselves favorable pharmacological properties may also be used, such as sulfur as a powder base, or zinc stearate as a component of ointment bases.

In the following examples, a number of typical forms of application for various uses are described.

EXAMPLE4 Wound dusting powder: 3.00 g of active substance, 5.0 g of zinc oxide and 41.9 g of rice starch are thoroughly mixed with 50.0 g of talcum which has been impregnated with 0.1 g of perfume. The mixture is passed through a suitable, fine sieve and again well mixed.

EXAMPLE 5 Antiseptic ointment: 3.0 g of active ingredient are triturated with 3.0 g of paraffin oil, and added to a mixture of 10.0 g of wool fat and 84.0 g of white vaseline, which has been melted at a moderate temperature. The mixture is allowed to cool while stirring.

EXAMPLE 6 Lozenges for the disinfection of the mouth and throat: 50.0 g of active substance are carefully mixed with 400.0 g of powdered sugar and the mixture is evenly moistened with a granulating solution of 8.0 g of gelatine and 2.0 g of glycerin in about g of water. The mass is granulated through a suitable sieve and dried. A sieved mixture of 3.0 g of highly dispersed silicic acid, 4.0 g of magnesium stearate, 0.7 g of flavoring and 42.3 g of talcum is added to the dry granulate and thoroughly mixed. The mixture is pressed into 1000 tablets.

EXAMPLE 7 Gargle concentrate: 5.0 g of active substance are dissolved in 60.0 g of 96 percent ethanol, 15.0 g' of glycerin and 0.3 g of flavoring are added and the solution is made up to 100.0 g with 19.7 g of distilled water. For gargling, about 20 drops of this concentrate are used in water.

EXAMPLE 8 Tablets for the disinfection of the intestines and the I urinal tract: To prepare 1000 tablets each containing 150 mg of active substance, first 150.0 g of active substance are thoroughly mixed with 60.0 g of maize starch and 35.0 g of lactose, and the mixture is evenly moistened with a granulating solution prepared from 5.0 g of gelatin and 3.0 g of glycerin in about 70 g of water. The mass is granulated through a suitable sieve and dried. The granulate is thoroughly mixed with a sieved mixture of 15.0 g of talcum, 10.0 g of dried maize starch and 2.0 g of magnesium stearate. The mixture is pressed into 1000 tablets.

EXAMPLE 9 Dragees for the disinfection of the intestines and the urinal tract: To prepare 1000 dragee cores, first 150.0 g of active substance are thoroughly mixed with 60.0 g of maize starch and 34.0 g of lactose. This mixtureis mixed with a binding agent consisting of 6.0 g of starch, 3.0 g of glycerin and about 54 g of distilled water, and the mass obtained is granulated through a suitable sieve and dried. The granulate is thoroughly mixed with a sieved mixture of 15.0 g of talcum, 10.0 g of maize starch and 2.0 g of magnesium stearate, and the mixture is pressed into 1000 dragee cores each weighing 280 mg.

The above cores are coated in a coating pan with a layer'consisting of: 2.000 g of shellac, 7.500 g of gum arabic, 0.180 g of dyestuff, 2.000 g of highly dispersed silicic acid, 35.00 g of talcum and 58.320 g of sugar. 1000 dragees are obtained each weighing 385 mg and containing 150 mg of active substance.

We claim: 1. An O,N-diphenyl-carbamic acid ester of the formula wherein R represents phenoxy substituted by from one to three identical or different halogen atoms selected from the group consisting of fluorine, chlorine and bromine, one of R R and R represents chlorine or bromine, and each of the others of R R and R represents hydrogen, chlorine or bromine, each of R and R represents hydrogen, fluorine, chlorine, bromine, lower alkyl, lower alkoxy, halogeno-lower alkyl, nitroor hydroxy, and R represents hydrogen, fluorine, chlorine, bromine, lower alkyl, lower alkoxy, di-lower alkylamino or hydroxy. 2. N-(3,4-dichlorophenyl)-carbamic acid-0-[ 2-(2 ',4 -di-chlorophenoxy)-5-chlorophenyl]-ester.

3. N-(3,5-dimethylphe y1)-carbamic acid-O-[2- (2 ,4 -dichlorophenoxy)-5-chloroplienyfiester.

4. N-(4-methylphenyl)-carbamic acid-0-[2-(4'- chlorophenoxy)-4-bromo-5-chlorophenyl]-ester.

5. N-(3,4-dichlorophenyl)-carbamic acid-0-[2-(2',4' -di-chlorophenoxy)-5-chlorophenyl]-ester.

6. N-( 3-nitro-4-chlorophenyl) carbamic acid-O-[Z- (2 T Y-dichlorophenoxy)-5-chlorophenyl]-ester.

7. N;(3-trifluoromethylphenyl)-carbamic acid-0-[2- 

2. N-(3,4-dichlorophenyl)-carbamic acid-0-(2-(2'' ,4''-di-chlorophenoxy)-5-chlorophenyl)-ester.
 3. N-(3,5-dimethylphenyl)-carbamic acid-0-(2-(2'' ,4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 4. N-(4-methylphenyl)-carbamic acid-0-(2-(4''-chlorophenoxy)-4-bromo-5-chlorophenyl)-ester.
 5. N-(3,4-dichlorophenyl)-carbamic acid-0-(2-(2'' ,4''-di-chlorophenoxy)-5-chlorophenyl)-ester.
 6. N-(3-nitro-4-chlorophenyl)-carbamic acid-0-(2-(2'' ,4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 7. N-(3-trifluoromethylphenyl)-carbamic acid-0-(2-(2'' ,4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 8. N-(4-hydroxyphenyl)-carbamic acid-0-(2-(2'' ,4''-dichlorophenoxy)-5-chlorophenyl)-ester.
 9. N-(2-methylphenyl)-carbamic acid-0-(2-(2'' ,4''-dichlorophenoxy)-4-bromo-5-chlorophenyl)-ester. 